CN101294216A - Substrate structure, oligomer probe array and methods for producing the same - Google Patents
Substrate structure, oligomer probe array and methods for producing the same Download PDFInfo
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- CN101294216A CN101294216A CNA2008100097266A CN200810009726A CN101294216A CN 101294216 A CN101294216 A CN 101294216A CN A2008100097266 A CNA2008100097266 A CN A2008100097266A CN 200810009726 A CN200810009726 A CN 200810009726A CN 101294216 A CN101294216 A CN 101294216A
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- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 125000002889 tridecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- GBGWDYMDIUDRDA-UHFFFAOYSA-N triethoxy(undec-10-enyl)silane Chemical compound CCO[Si](OCC)(OCC)CCCCCCCCCC=C GBGWDYMDIUDRDA-UHFFFAOYSA-N 0.000 description 1
- JUHLJPNKMLPGMH-UHFFFAOYSA-N undec-10-enylsilane Chemical compound [SiH3]CCCCCCCCCC=C JUHLJPNKMLPGMH-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 238000004804 winding Methods 0.000 description 1
- 229910001928 zirconium oxide Inorganic materials 0.000 description 1
- GFQYVLUOOAAOGM-UHFFFAOYSA-N zirconium(iv) silicate Chemical compound [Zr+4].[O-][Si]([O-])([O-])[O-] GFQYVLUOOAAOGM-UHFFFAOYSA-N 0.000 description 1
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- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/0046—Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6813—Hybridisation assays
- C12Q1/6834—Enzymatic or biochemical coupling of nucleic acids to a solid phase
- C12Q1/6837—Enzymatic or biochemical coupling of nucleic acids to a solid phase using probe arrays or probe chips
-
- C—CHEMISTRY; METALLURGY
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- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
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- C40B50/14—Solid phase synthesis, i.e. wherein one or more library building blocks are bound to a solid support during library creation; Particular methods of cleavage from the solid support
- C40B50/18—Solid phase synthesis, i.e. wherein one or more library building blocks are bound to a solid support during library creation; Particular methods of cleavage from the solid support using a particular method of attachment to the solid support
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Abstract
Disclosed are substrate structures, an oligomer probe array and methods of producing the same. The substrate structure may include a substrate, and an intermediate film. The intermediate film comprises either of the compounds with the following general structures: wherein R1 is alkyl, aryl, alkoxy, nitrile, ester, phenyl, hydroxyl, aliphatic lactone, cycloalkyl or cycloalkenyl, R2 is alkyl, aryl, alkoxy, nitrile, ester, phenyl, hydroxyl, aliphatic lactone, cycloalkyl or cycloalkenyl, and X is coupled with the substrate directly or via an immobilization layer, Y is coupled with a linker, spacer, or an oligomer.
Description
Technical field
One exemplary embodiment relates to substrat structure, low polymer probe array and manufacture method thereof.
Background technology
Along with the development of genome project, had been found that various organic genome nucleotide sequences, this has increased the interest of utilizing microarray.Microarray can be used to carry out genetic expression die mould and genotype, and to detect sudden change and polymorphic, for example, SNP with analysing protein and peptide, screens the potential medicine, and exploitation and manufacturing novel drugs.
In order to develop this low polymer probe array, biomaterial and semi-conductor, the effect at the molecule interface between the silicon for example is for effectively and to utilize the inherent function of the biomaterial of the inherent nature that comprises biomaterial fully be very important.For example, developed and allow low polymer probe and substrate to be easy to be coupled and conduct is used to provide the compound of space allowance between low polymer probe and the target sample and of great use compound.
In this low polymer probe, for example, the biomaterial of the biomaterial with micron scale fixed correlation in the predetermined or given area, for example DNA chip and/or protein chip are very important.Utilize low polymer probe array, can analyze the type of the genetic information from gene to the Nucleotide scope, gene and Nucleotide are the minimum component units of DNA here.Therefore, because size, probe unit can be reduced to a few approximately μ m from about tens μ m.
Summary of the invention
One exemplary embodiment is provided for increasing the substrat structure of the high integrated low polymer probe array of reaction yield.Other one exemplary embodiment provides a kind of low polymer probe array that utilizes this substrat structure to form.One exemplary embodiment provides the method that is used for making this substrat structure and low polymer probe array respectively.One exemplary embodiment be not limited to above-mentioned those, and by following description, those skilled in the art will more be expressly understood one exemplary embodiment.
According to one exemplary embodiment, a kind of substrat structure is provided, it can comprise the intermediate coat that comprises the chemical structure of being represented by following structural formula 1 on substrate and this substrate.
＜structural formula 1 〉
(R wherein
1Be alkyl, aromatic base, alkoxyl group, nitrile, ester, phenyl, hydroxyl, aliphatics lactones, cycloalkyl or cycloalkenyl group,
R
2Be alkyl, aromatic base, alkoxyl group, nitrile, ester, phenyl, hydroxyl, aliphatics lactones, cycloalkyl or cycloalkenyl group and
X and substrate directly or via immovable bed are coupled).
According to one exemplary embodiment, a kind of substrat structure is provided, it can comprise the intermediate coat that comprises the chemical structure of being represented by following structural formula 2 on substrate and this substrate.
＜structural formula 2 〉
(R wherein
1Be alkyl, aromatic base, alkoxyl group, nitrile, ester, phenyl, hydroxyl, aliphatics lactones, cycloalkyl or cycloalkenyl group,
R
2Be alkyl, aromatic base, alkoxyl group, nitrile, ester, phenyl, hydroxyl, aliphatics lactones, cycloalkyl or cycloalkenyl group,
Y and junctor, spacer or low polymer probe coupling and
X directly or via immovable bed and substrate is coupled).
According to one exemplary embodiment, intermediate coat on a kind of substrat structure and the substrate is provided, this substrat structure can comprise have with low polymer probe coupled region of activation and not with the substrate in low polymer probe coupled disactivation district, this intermediate coat comprise on the region of activation by the chemical structure of structural formula 2 expressions and the chemical structure in the disactivation district by structural formula 1 expression.
＜structural formula 1 〉
＜structural formula 2 〉
(R wherein
1Be alkyl, aromatic base, alkoxyl group, nitrile, ester, phenyl, hydroxyl, aliphatics lactones, cycloalkyl or cycloalkenyl group,
R
2Be alkyl, aromatic base, alkoxyl group, nitrile, ester, phenyl, hydroxyl, aliphatics lactones, cycloalkyl or cycloalkenyl group,
Y and junctor, spacer or low polymer probe coupling and
X directly or via immovable bed and substrate is coupled).
According to one exemplary embodiment, a kind of low polymer probe array is arranged, it can comprise the substrat structure of one exemplary embodiment and the low polymer probe on the substrate.
According to one exemplary embodiment, a kind of method of making substrat structure is provided, it can comprise provides substrate and form the intermediate coat that comprises by the chemical structure of following structural formula 1 expression on substrate.
＜structural formula 1 〉
(R wherein
1Be alkyl, aromatic base, alkoxyl group, nitrile, ester, phenyl, hydroxyl, aliphatics lactones, cycloalkyl or cycloalkenyl group,
R
2Be alkyl, aromatic base, alkoxyl group, nitrile, ester, phenyl, hydroxyl, aliphatics lactones, cycloalkyl or cycloalkenyl group and
X directly or via immovable bed and substrate is coupled).
According to one exemplary embodiment, a kind of method of making low polymer probe array is provided, it can comprise: make substrat structure, exposure at least a portion intermediate coat according to one exemplary embodiment and intermediate coat and the low polymer probe coupling that at least a portion is exposed.
The details of other one exemplary embodiment is included among detailed description and the figure.
Description of drawings
In conjunction with the accompanying drawings, by following detailed, will more be expressly understood one exemplary embodiment.
Fig. 1 a-5h represents as nonrestrictive one exemplary embodiment described herein.
Fig. 1 a to 1d is the sectional view according to the microarray of one exemplary embodiment.
Fig. 2 a to 2e and Fig. 3 a to 3e are the sectional views according to the low polymer probe array of one exemplary embodiment.
Fig. 4 is the precedence diagram that is provided to show according to the manufacturing low polymer probe array method of one exemplary embodiment.
Fig. 5 a to 5h is used for order sectional view according to the method for the manufacturing substrat structure of one exemplary embodiment is shown.
Should be noted that these figure be intended to illustrate the general feature of the method, structure and/or the material that in some one exemplary embodiment, utilize and replenish below the written description that provides.Yet these figure are not pro rata, and can not accurately reflect precision architecture or the performance characteristic of arbitrary given embodiment, and should not be interpreted as defining or limiting the scope or the character of the value that is comprised by one exemplary embodiment.Particularly, for the sake of clarity, can reduce or amplify the relative thickness and the position of molecule, layer, zone and/or textural element.In different figure, use similar or identical Reference numeral to be intended to indicate and have similar or identical element or feature.
Embodiment
By the detailed description and the accompanying drawings, can more easily understand the advantage and the feature that realize one exemplary embodiment of the present invention and method with reference to following one exemplary embodiment.Yet one exemplary embodiment can be implemented with many different modes, and should not be construed and be limited to the embodiment that lists here.On the contrary, provide these embodiment, so that the disclosure is more abundant and comprehensive, and pass on the idea of one exemplary embodiment all sidedly, and one exemplary embodiment only defines by the claim of adhering to those skilled in the art.In an exemplary embodiment, when to already known processes, device architecture with when the detailed description of bonded technology makes that the purport of one exemplary embodiment is not known, will omit these descriptions here.
Term used herein only is the purpose that is used to describe specific embodiment, and is not meant the restriction one exemplary embodiment.As used herein, singulative refers to and also comprises plural form, unless clearly indication in addition in the context.Will be further understood that, term " comprises " and/or " comprising ", when using in this manual, indicate the element, step, operation and/or the parts that there are regulation, there are not other one or more other elements, step, operation and/or parts but do not get rid of.In addition, term " and/or " comprise one or more relevant list projects arbitrarily and all combinations.In addition, run through identical in full numeral indication components identical.Thus, identical Reference numeral is indicated components identical, and has omitted the detailed description of these elements for convenience.
With reference to the sectional view and/or the synoptic diagram that show one exemplary embodiment, one exemplary embodiment will be described.Thus, according to manufacturing technology and/or tolerance, can revise the section of explanatory view.For example, it not is the scope of restriction one exemplary embodiment that one exemplary embodiment refers to, but covers because all changes and the modification that the variation of manufacturing process causes.For convenience, the element among the figure of one exemplary embodiment can amplify or dwindle a little.Hereinafter, will describe one exemplary embodiment in detail with reference to the accompanying drawings.
Should be appreciated that though the term first, second, third, etc. are used for describing different elements, parts, zone, layer and/or cross section here, these elements, parts, zone, layer and/or cross section should not limited by these terms.These terms only are used for distinguishing element, parts, zone, layer or a cross section and another zone, layer or cross section.Thus, first element, parts, zone, layer or the cross section of Tao Luning under the prerequisite of the instruction that does not depart from one exemplary embodiment, can be called second element, parts, zone, layer or cross section hereinafter.
The space relative terms, for example " under ", " below ", " following ", " on ", " top " etc., be used for being convenient to the description of an element or feature here to the relation of other element shown in the figure or feature.Should be understood that the space relative terms refers to comprise the orientation of describing in figure uses or the different azimuth of the device during operation.For example, if the device reverse turn among the figure, then be described as other element or feature " below " or the element of " below " then be positioned at " top " of other element or feature.Thus, exemplary term " ... following " can comprise two orientation, above and below.Therefore this device can and explain space used herein relative descriptors with other direction location (revolve turn 90 degrees or in other orientation).
Term used herein only is used to describe specific embodiment, and is not meant the restriction one exemplary embodiment.As used herein, the indefinite article of singulative and definite article refer to and also comprise plural form, unless alternate manner pointed out clearly in context.Should be further understood that, the term of Shi Yonging " comprises " and/or " comprising " in this manual, refer to and have described feature, integral body, step, operation, element and/or parts, have or add one or more further features, integral body, step, operation, element, parts and/or their group but do not get rid of.
Here with reference to the sectional view that schematically illustrates that is the desirable embodiment (and intermediate structure) of one exemplary embodiment one exemplary embodiment is described.Equally, for example, expect as the change of shape of manufacturing technology and/or tolerance limit result's explanation.Thus, one exemplary embodiment should not be configured to be limited to the specified shape in the zone of explanation here, but comprises the form variations that is for example caused by manufacturing.For example, be exemplified as the orthogonal injection region, generally have circle or curvilinear characteristic and/or be the gradient of implantation concentration at its edge rather than change from the binary that is injected into non-injection region.Equally, can cause at buried regions and some injections in the zone between the surface that takes place to inject by injecting the buried regions that forms.Thus, the zone shown in the figure is schematically in essence, and their shape is not meant the true form in the zone that device is described and is not meant the scope of restriction one exemplary embodiment.
Except as otherwise noted, otherwise all terms used herein have (comprising technology and scientific terminology) the identical meaning of those of ordinary skills' common sense that belongs to one exemplary embodiment.Will be further understood that, those terms that define in for example normally used dictionary, should be interpreted as having with the association area context in the meaning of aggregatio mentium, and should not be construed as the ideal or the meaning of form too, unless clear and definite so definition here.
Fig. 1 a to 1c is the sectional view according to the low polymer probe array of one exemplary embodiment.With reference to figure 1a, be used for substrate 100 according to the low polymer probe array of one exemplary embodiment and can comprise substrate 110 and comprise the intermediate coat 130 that is formed on the substrate 110 by the chemical structure of following structural formula 1 expression.
＜structural formula 1 〉
(R wherein
1Be hydroxyl, alkyl, aromatic base, alkoxyl group, nitrile, ester, phenyl, hydroxyl, aliphatics lactones, cycloalkyl or cycloalkenyl group,
R
2Be alkyl, aromatic base, alkoxyl group, nitrile, ester, phenyl, hydroxyl, aliphatics lactones, cycloalkyl or cycloalkenyl group and
X directly or via immovable bed and substrate is coupled; With
R
1Or R
2Can by to be selected from by
The expression compound dialkylene be selected from by
The dienophile of the compound of expression carries out Diels-Alder reaction and forms.
Can form intermediate coat 130 by X in the direct couple junction structure formula 1 and substrate 110.Coupling refers to chemical bond, for example, and covalent linkage.The intermediate coat 130 that is formed on the substrate 110 can have the chemical structure of being represented by structural formula 1.Chemical structure by structural formula 1 expression can comprise the diazonium ketone group.If the radiation exposure of about 193nm or about 248nm is on the intermediate coat 130 that comprises the diazonium ketone group, then diazo can form carboxylic acid by series reaction.But the intermediate coat 130 shown in Fig. 1 can be included in and form carboxylic acid diazonium ketone group before.
＜scheme 1 〉
In the intermediate coat 130 that comprises the diazonium ketone group, can form carboxyl by staying diazo.As a result, intermediate coat 130 with can with the functional group coupling of carboxyl reaction.Can comprise amido and hydroxyl with the example of the functional group of carboxyl reaction, but be not limited thereto.Thus, comprise low polymer probe, junctor, spacer, particulate and/or the nano particle of the functional group of the carboxyl that can be coupled by coupling, the substrate 100 that is used for low polymer probe array can be used for low polymer probe array.If intermediate coat 130 and low polymer probe coupling, then intermediate coat 130 can be used as junctor or spacer.For example, intermediate coat 130 can provide interaction freely, and for example, the hydridization of low polymer probe and target sample is as junctor in the low polymer probe array or spacer.
And in some figure, having demonstrated forms the one exemplary embodiment of intermediate coat 130 at all surfaces of substrate, but this intermediate coat 130 can partly be formed on a part of surface of substrate 110 according to purpose.For example, intermediate coat 130 can form the tetragonal matrix with regular spaces.But square only is an example, and it is not restricted to above shape.Also can be circular, and can use comparably hereinafter.
Hereinafter, will describe substrat structure 101 in detail with reference to figure 1b according to one exemplary embodiment.Fig. 1 b is the sectional view according to the substrat structure of one exemplary embodiment.Substrat structure 101 shown in Fig. 1 b can have and the substrate 100 essentially identical structures that are used for the low polymer probe array shown in Fig. 1 a, except following.In following examples,, then can omit or simplify its description if repeat the composition material of aforesaid element here once more.
And the immovable bed 120 of having demonstrated is formed on the one exemplary embodiment of all surfaces of substrate, but it can partly be formed on the part of substrate according to some purpose.This mode can be basic identical with the situation of intermediate coat 130, and can use comparably hereinafter.
Hereinafter, will describe substrat structure 102 in detail with reference to figure 1c according to one exemplary embodiment.Fig. 1 c is the sectional view according to the substrat structure of one exemplary embodiment.Substrat structure 102 shown in Fig. 1 c can have and the substrat structure 101 essentially identical structures shown in Fig. 1 b, except following.
Can comprise substrate 111, be formed on the immovable bed 121 on the substrate 111 and comprise intermediate coat 131 according to the substrat structure 102 of one exemplary embodiment by the chemical structure of structural formula 1 expression with three-dimensional surface.Can comprise three-dimensional surface on the substrate 111 according to the substrat structure 102 of one exemplary embodiment.Intermediate coat 131 can be formed on the three-dimensional surface of substrate 111.Substrate 111, immovable bed 121 and intermediate coat 131 can have three-dimensional surface, thus by with represent according to the different Reference numeral of the intermediate coat 130 of substrate 110, immovable bed 120 and the substrate 100 of the low polymer probe array of one exemplary embodiment.Yet this is unique difference, and is same, also should the descriptions thereof are omitted.If substrate 111 has three-dimensional surface, then low polymer probe can highly be integrated in the substrat structure 102, and this can reduce design rule, and can increase reaction yield.Below, will be with reference to the low polymer probe array of each figure description according to one exemplary embodiment.
And, shown in Fig. 1 D, be used for substrate 103 according to the low polymer probe array of one exemplary embodiment and can comprise three-dimensional surface in the substrate.And the cross section of three-dimensional surface has zigzag shape, but it also can have three-dimensional structure.For example, this surface can comprise curved surface.
Fig. 2 a to 2d and Fig. 3 a to 3b are the sectional views according to the low polymer probe array of one exemplary embodiment.With reference to figure 2a, according to the low polymer probe array 200 of one exemplary embodiment can comprise substrate 110, be formed on the low polymer probe 160 on the substrate 110 and be inserted in substrate 110 and low polymer probe 160 between comprise intermediate coat 230 by the chemical structure of structural formula 2 expressions.
＜structural formula 2 〉
(R wherein
1Be alkyl, aromatic base, alkoxyl group, nitrile, ester, phenyl, hydroxyl, aliphatics lactones, cycloalkyl or cycloalkenyl group,
R
2Be alkyl, aromatic base, alkoxyl group, nitrile, ester, phenyl, hydroxyl, aliphatics lactones, cycloalkyl or cycloalkenyl group,
Y and junctor, spacer or low polymer probe coupling and
X directly or via immovable bed and substrate is coupled).
Substrate 110 can be basic identical with the substrat structure 101 shown in Fig. 1 b, and thus also can the descriptions thereof are omitted.Intermediate coat 230 can have the chemical structure by structural formula 2 expressions.Under the situation of the substrate 100 that is used for the low polymer probe array shown in Fig. 1 a, the intermediate coat 130 that is formed on the substrate 110 can have the chemical structure of being represented by the structural formula 1 that comprises the diazonium ketone group.Yet, in case exposure just can convert the chemical structure by structural formula 1 expression that comprises the diazonium ketone group to carboxyl for light, and after the exposure carboxyl, coupling low polymer probe 160.Because low polymer probe array shown in Fig. 2 a 200 and low polymer probe 160 couplings, different with the substrate 100 that is used for the low polymer probe array shown in Fig. 1 a, low polymer probe array 200 can have the chemical structure by structural formula 2 expressions, and this is owing to mechanism causes, shown in scheme 1.Intermediate coat 230 can be used as the junctor (junctor molecule) that is used to connect substrate 110 and low polymer probe 160 or is used to provide spacer with the space allowance of target sample hydridization needs.For example, intermediate coat 230 can with low polymer probe coupling so that the space allowance that needs with target sample hydridization to be provided.
Amino acid can be L-, D-and/or achirality amino acid, and it is that nature is found.Alternatively, amino acid can be improved amino acid and/or amino acid whose analogue.Peptide can be the compound that is obtained by the amido linkage between amino acid whose carboxyl and another the amino acid whose amino.Low polymer probe 160 can be made by two or more nucleosides, Nucleotide, amino acid and/or peptide.
In low polymer probe 160, intermediate coat 230 and low polymer probe 160 can directly be coupled, thus, low polymer probe 160 can comprise can with the carboxyl coupled functional group of intermediate coat 230.Can comprise amido and hydroxyl with the example of carboxyl coupled functional group, but be not limited thereto.This coupling refers to the covalent linkage in the chemical bond.
Hereinafter, will be with reference to the low polymer probe array 201 of figure 2b description according to one exemplary embodiment.Fig. 2 b is the sectional view according to the low polymer probe array of one exemplary embodiment.Low polymer probe array 201 shown in Fig. 2 b can have and low polymer probe array 200 essentially identical structures, except following.
Low polymer probe array 201 according to one exemplary embodiment can comprise substrate 110, be formed on immovable bed 120 on the substrate 110, be formed on the immovable bed 120 comprise by the intermediate coat 230 of the chemical structure of structural formula 2 expressions and with intermediate coat 230 coupled low polymer probes 160.In low polymer probe array 201, intermediate coat 230 can be via immovable bed 120 and substrate 110 couplings.Immovable bed 120 can be the silicone resin layer of being made by for example silicone resin.For example, in structural formula 1, immovable bed 120 can be-Si (OR)
3(wherein R is an alkyl).Exist immovable bed 120 can make intermediate coat 130 easier, and improved the function of intermediate coat 130, therefore increased reaction yield with the sample example as junctor or spacer with the coupling of substrate 110.
Hereinafter, will be with reference to the low polymer probe array 202 of figure 2c description according to one exemplary embodiment.Fig. 2 c is the sectional view according to the low polymer probe array of one exemplary embodiment.Low polymer probe array 202 shown in Fig. 2 c can have and the low polymer probe array 201 essentially identical structures shown in Fig. 2 b, except following.
According to the low polymer probe array 202 of one exemplary embodiment can comprise substrate 111 with three-dimensional surface, be formed on immovable bed 121 on the substrate 111, be formed on the immovable bed 121 comprise by the intermediate coat 231 of the chemical structure of structural formula 2 expressions and with intermediate coat 231 coupled low polymer probes 160.Substrate 111, immovable bed 121 and intermediate coat 231 can have three-dimensional surface, are represented by the reference marker different with the substrate 110 of the low polymer probe pin row 200 shown in Fig. 2 b, immovable bed 120 and intermediate coat 230 thus.Yet, only difference that Here it is, same, also should the descriptions thereof are omitted.If substrate 111 has three-dimensional surface, then low polymer probe 160 can highly be integrated in the low polymer probe array 202, and it can cause design rule to reduce and increase reaction yield.
Hereinafter, will be with reference to the low polymer probe array 203 of figure 2d description according to one exemplary embodiment.Fig. 2 d is the sectional view according to the low polymer probe array of one exemplary embodiment.Low polymer probe array 203 shown in Fig. 2 d can have and the low polymer probe array 202 essentially identical structures shown in Fig. 2 c, except following.
According to the low polymer probe array 203 of one exemplary embodiment can comprise substrate 111 with three-dimensional surface, be formed on immovable bed 121 on the substrate 111, be formed on the immovable bed 121 comprise by the intermediate coat 231 of the chemical structure of structural formula 2 expressions, with intermediate coat 231 coupled junctors 140 and with junctor 140 coupled low polymer probes 160.And, shown in Fig. 2 E, can comprise three-dimensional surface in the substrate 112 according to the low polymer probe array 204 of one exemplary embodiment.And, form three-dimensional surface as surface with three-dimensional structure, it is just enough for example to form for example circular surface of curved surface.
In Fig. 2 d and Fig. 2 E, show junctor 140, but be not limited thereto, spacer, microcosmic particle and/or nano particle can connect intermediate coat 231 and low polymer probe 160 thus.Junctor 140, spacer, microcosmic particle and/or nano particle can comprise can with substrate or low polymer probe 160 coupled functional groups.
Hereinafter, will be with reference to the low polymer probe array 300 of figure 3a description according to one exemplary embodiment.Low polymer probe array 300 shown in Fig. 3 a can have the structure identical with the low polymer probe array 200 shown in Fig. 2 a, except following.With reference to figure 3a, low polymer probe array 300 according to one exemplary embodiment can comprise low polymer probe 160, comprise with low polymer probe 160 coupled region of activation A and not with the substrate 310 of low polymer probe 160 coupled disactivation district B and be included in region of activation A go up by the chemical structure of structural formula 2 expressions and on disactivation district B by the intermediate coat 330 of the chemical structure of following structural formula 1 expression.
＜structural formula 1 〉
＜structural formula 2 〉
(R wherein
1Be alkyl, aromatic base, alkoxyl group, nitrile, ester, phenyl, hydroxyl, aliphatics lactones, cycloalkyl or cycloalkenyl group,
R
2Be alkyl, aromatic base, alkoxyl group, nitrile, ester, phenyl, hydroxyl, aliphatics lactones, cycloalkyl or cycloalkenyl group,
Y and junctor, spacer or low polymer probe coupling and
X directly or via immovable bed and substrate is coupled).
For example, according to the substrate 310 of the low polymer probe array 300 of one exemplary embodiment can comprise with low polymer probe coupled region of activation A and not with low polymer probe 160 coupled disactivation district B.Intermediate coat 330 can comprise have be formed on the A of region of activation by the regional 330a of the chemical structure of structural formula 2 expression and have a regional 330b that is formed on the disactivation district B by the chemical structure of following structural formula 1 expression.The intermediate coat 330a that is formed on the A of region of activation can be coupled with low polymer probe 160.The intermediate coat 330b that is formed on the zone that comprises the chemical structure of being represented by following structural formula 1 on the disactivation district B can not be coupled with low polymer probe 160.Except predetermined or given area 330a, low polymer probe 160 can be not and the whole surface coupling of intermediate coat 330, and optionally activating area is provided thus, and this makes it possible to have multiple low polymer probe 160, with softer with the target sample reaction.Intermediate coat 330 can be used as the junctor (link molecule) that is used for connecting substrate 310 and low polymer probe 160, or is used to provide the spacer with the needed space of target sample hydridization allowance.
The substrate 310 of the low polymer probe array 300 shown in Fig. 3 a can be different with intermediate coat 230 with the substrate 110 of the low polymer probe array 200 shown in Fig. 2 a with intermediate coat 330, represent with the Reference numeral that differs from one another thus.Yet except above-described difference, they are basic identical, therefore, also will omit the description to it.Hereinafter, will be with reference to the low polymer probe array 301 of figure 3b description according to one exemplary embodiment.Except following, the low polymer probe array 301 shown in Fig. 3 b has and the low polymer probe array 300 essentially identical structures shown in Fig. 3 a.
With reference to figure 3b, low polymer probe array 301 can comprise low polymer probe 160, comprise with low polymer probe 160 coupled region of activation A and not with the substrate 310 of low polymer probe 160 coupled disactivation district B, be formed on the immovable bed 120 on the substrate 310 and comprise be formed on the A of region of activation by the regional 330a of the chemical structure of structural formula 2 expressions and comprise the intermediate coat 330 that is formed on the disactivation district B by the regional 330b of the chemical structure of following structural formula 1 expression.For example, in the low polymer probe array 301 according to one exemplary embodiment, intermediate coat 330 can be by immovable bed 120 and substrate 310 couplings.Immovable bed 120 can be the silicone resin layer of for example being made by silicone resin.For example, in structural formula 1, immovable bed can be-Si (OR)
3(wherein R is an alkyl).Exist immovable bed 120 can make intermediate coat 130 easier, and improve the function of intermediate coat 130 as junctor or spacer with substrate 110 couplings, thus the reaction yield of increase and target sample.
Hereinafter, will be with reference to the low polymer probe array 302 of figure 3c description according to one exemplary embodiment.Except following, the low polymer probe array 302 shown in Fig. 3 c can have and the low polymer probe array 300 essentially identical structures shown in Fig. 3 a.With reference to figure 3c, the low polymer probe array 302 shown in Fig. 3 c is with the different of low polymer probe array 301 shown in Fig. 3 b: substrate 311 can have three-dimensional surface.Because substrate 311 has three-dimensional surface, so the intermediate coat 331 that is formed on the lip-deep immovable beds 121 of substrate 311 and is formed on the immovable bed 121 also can have three-dimensional surface, use the Reference numeral different to represent thus with the intermediate coat 330 of the low polymer probe array 301 shown in Fig. 3 b.Yet the low polymer probe array 301 shown in the low polymer probe array 302 shown in Fig. 3 c and Fig. 3 b can be basic identical.
If substrate 311 has three-dimensional surface, then low polymer probe 160 can highly be integrated into low polymer probe array 302, and this can reduce size and increase reaction yield.Hereinafter, will be with reference to the low polymer probe array 303 of figure 3d description according to one exemplary embodiment.Except following, the low polymer probe array 303 shown in Fig. 3 d can have and the low polymer probe array 302 essentially identical structures shown in Fig. 3 c.
With reference to figure 3d, the low polymer probe array 303 shown in Fig. 3 d is with the different of low polymer probe array 302 shown in Fig. 3 c: low polymer probe 160 can be via junctor 140 and intermediate coat 331 couplings.In Fig. 3 d, show junctor 140, but be not limited to this, thus, spacer, microcosmic particle and/or nano particle can connect intermediate coat 331 and low polymer probe 160.Junctor 140, spacer, microcosmic particle and/or nano particle can comprise can with substrate or low polymer probe 160 coupled functional groups, this can be so that low polymer probe 1 be easier with the substrate coupling, perhaps for providing the space allowance with target sample hydridization.As in preceding argumentation, intermediate coat 331 can be identical with the function of junctor 140, spacer, microcosmic particle and/or nano particle, but also can be coupled, the low polymer probe array that has improved reaction yield is provided thus with junctor 140, spacer, microcosmic particle and/or nano particle.
In addition, shown in Fig. 3 E, can in substrate 312, comprise three-dimensional surface according to the low polymer probe array 304 of one exemplary embodiment.In addition, this three-dimensional surface can be formed curved surface, and it is just enough to have a surface of three-dimensional structure, as mentioned above.With reference to figure 4 and Fig. 5 a to 5h, hereinafter,, will method that make low polymer probe array according to one exemplary embodiment be described with reference to institute's drawings attached.
Fig. 4 is used for describing the precedence diagram of making the method for low polymer probe array according to one exemplary embodiment, and Fig. 5 a to 5h is used for describing in proper order the sectional view that illustrates according to the manufacturing low polymer probe array method of one exemplary embodiment.As shown in Figure 4, comprise according to the method for the manufacturing low polymer probe array 303 of one exemplary embodiment and substrate 310 (S10) is provided, forms the three-dimensional surface (S20) of substrate 310, on substrate 311, forms immovable bed 121 (S30), on immovable bed 121, forms intermediate coat 331 (S40), exposes at least a portion intermediate coat 311 (S50), coupling intermediate coat 331a and junctor 140 (S60) and coupled junctor 140 and low polymer probe 160 couplings (S70) with three-dimensional surface.
Shown in Fig. 5 a, can provide substrate 310 (S10).During hydridization technology, can minimize substrate 310 or reduce unwanted nonspecific key, and further to make the number of nonspecific key be zero substantially.This substrate can be with visible light and/or UV material transparent are made.Substrate 310 can be flexible or the inflexible substrate.The example of flexible substrate can comprise barrier film or the plastic film of being made by nylon and/or nitrocotton.The example of rigid substrate can comprise the transparent glass substrate of silicon substrate and/or soda-lime glass.Under the situation of silicon substrate and/or transparent glass substrate, during hydridization is handled, may produce nonspecific key hardly.In addition, under the situation of transparent glass substrate, it is transparent to visible light and/or UV, advantageously detects fluorescent mark thus.Silicon substrate and/or transparent glass substrate may be favourable, can be applied to this under situation about not revising because generally be used for making the technology or the photoetching process of the various manufacturing films of semiconducter device or LCD panel.Shown in Fig. 5 b, can on the surface of substrate 310, form three-dimensional surface (S20).
Though do not illustrate in the drawings, can form polymer layer in order on substrate 310, to form three-dimensional surface.The example of polymer layer that is used for forming the three-dimensional surface of substrate 310 can comprise: silicon oxide film, for example, PE-TEOS film, HDP oxide film, P-SiH
4Oxide film and heat oxide film; Silicate, for example hafnium silicate and zirconium silicate; The metal oxynitride film, for example, silicon oxynitride film and nitrogen zirconium oxide film; Metal oxide film, for example oxidation titanium film, tantalum-oxide film, pellumina, hafnia film, zirconium oxide film and ITO; Polyimide; Polyamines; Metal, for example gold and silver, copper and palladium; Or polystyrene, polyacrylic acid and polyvinyls.Can use stable depositing operation during being used for forming the technology of the semi-conductive technology of manufacturing of three-dimensional surface or the LCD that manufacturing is used for polymer layer, for example, CVD (chemical vapour deposition), SACVD (subatmospheric chemical vapour deposition), LPCVD (low-pressure chemical vapor deposition), PECVD (plasma enhanced chemical vapor deposition), sputter and/or spin coating.Can use and to stablize the material that is formed on the substrate 310.After forming photoresist film, can be by utilizing the photomask photoresist film that in the projection exposure device, exposes, wherein this photomask is according to the three-D pattern preparation that will form, and has obtained the three-dimensional surface of substrate thus.The three-D pattern that forms on substrate surface for example can be a checkerboard pattern.
Thereafter, shown in Fig. 5 c, immovable bed 121 can be formed on the substrate 311 with three-dimensional surface (S30).Immovable bed 121 for example can be the silicone resin layer of being made by silicone resin, for example, comprises Si (OR)
3The layer of (wherein R is an alkyl).Compare with the situation of not inserting immovable bed 121, by inserting immovable bed 121, intermediate coat 331 (seeing Fig. 5 d) can more easily be coupled with substrate 311, has increased the reaction yield with target sample thus.If the surface of substrate 311 has, for example, hydroxyl, the SiO (OR) of the immovable bed 121 that can be coupled
3Base forms immovable bed 121 thus on the surface of substrate 311.
For example, will describe wherein silicone resin layer, for example comprise-Si (OR)
3Preparation method as immovable bed 121.For example, by narrow slit coating process and/or spin coating proceeding, can form the silicone resin layer.This narrow slit coating process and/or spin coating proceeding can be the same with oxidizing process or chemical vapor deposition method or more more convenient than it, and can reduce the treatment time, increased processing output thus.Can cure the silicone resin layer that forms thus.Stoving temperature can arrive in about 400 ℃ scope at about 100 ℃, and for example about 200 ℃ are arrived in about 300 ℃ scope.This time of curing can be at about 30 seconds in about 1 hour scope.As the result who cures, silicone resin can be connected in series each other, and this can increase the rigidity of silicone resin layer.
As Fig. 5 d shown in, can on immovable bed 121 form the intermediate coat 331 (S40) that comprise by the chemical structure of structural formula 1 expression thereafter.Can form the chemical that is used for forming the intermediate coat 331 that comprises the chemical structure of representing by structural formula in the following method.
＜structural formula 1 〉
(R wherein
1Be alkyl, aryl, alkoxyl group, nitrile, ester, phenyl, hydroxyl, aliphatics lactone, cycloalkyl or thiazolinyl,
R
2Be alkyl, aryl, alkoxyl group, nitrile, ester, phenyl, hydroxyl, aliphatics lactone, cycloalkyl or thiazolinyl and
X is directly or via immovable bed and substrate coupled position).
The chemical that is used to form the intermediate coat 331 that comprises the chemical structure of being represented by structural formula 1 can comprise the diazonium ketone group.Description is used for preparing the method for the compound that comprises ketone group.By making dienophile compound and conjugated diene compound carry out the Diels-Alder reaction of cyclisation; with the synthetic diketone that comprises the diketo structure; and at about 0 ℃; under normal pressure; diketone and diazo transfer reagent are for example reacted to carboxyl benzenesulfonyl trinitride, p-toluenesulfonyl trinitride with to the dodecylbenzene sulfuryl azide; continue 30 minutes to about 60 minutes, can form the diazonium ketone group.
Diels-Alder reaction (Diels, O., Alder, K. (1928) " Synthesen in derhydroaromatischen Reihe " Liebigs Annalen der Chemie 460 (1), be by having 1 of two keys or triple-linked dienophile and conjugated diolefine 98-122), the 4-addition reaction prepares the reaction of six-ring compound.The mechanism of Diels-Alder reaction is not clear, but reaction itself can be fast relatively, and may need also may not need catalyzer.
For example, be contained in formation under the situation of diazonium ketone group of intermediate coat 331, can be selected from by
The expression compound dialkylene and be selected from by
The dienophile of the compound of expression carries out Diels-Alder reaction, to form the six-ring compound.If a compound is a diene, then another compound can be a dienophile.
For example, shown in following scheme 2, cyclopentadiene can be added to methyl vinyl ketone solution, and can prepare 2-ethanoyl-5-norbornylene by Diels-Alder reaction.Product can react with dimethyl carbonate, with preparation methyl (5-norbornene)-3-oxo-propionic ester.
＜scheme 2 〉
The intermediate coat 331 that forms the compound that comprises diketo can be coupled with the immovable bed 121 on the substrate 311.This coupling can be the covalent linkage in the chemical bond.By the reaction of immovable bed 121 and intermediate coat 331 lip-deep various functional groups, intermediate coat 331 and immovable bed 121 can be coupled.For example, by Diels-Alder reaction, intermediate coat 331 and immovable bed 121 can be coupled with dienophile and diene.
Then; after mixing acetonitrile and methyl (5-norbornene)-3-oxo-propionic ester and cooling off this mixture; utilize triethylamine and as diazo transfer reagent can make methyl (5-norbornene)-2-diazonium-oxo-propionic ester to carboxyl benzenesulfonyl trinitride, illustrated in this scheme 3 below.
＜scheme 3 〉
For example, with reference to chemical structure, can be dialkylene as the alkene of the triethoxy on the immovable bed 121 that forms on the substrate 311 (10-undecenyl)-silane by 3 expressions of following structural formula.(13-hydroxyl-2-oxygen tridecyl)-purine can be a dienophile to comprise the 2-of the intermediate coat 331 of diazonium ketone group.Can be by Diels-Alder reaction the be coupled dialkylene of immovable bed 121 and the dienophile base of intermediate coat 331.
＜structural formula 3 〉
Except Diels-Alder reaction, can be by various functional group coupling immovable beds 121 and intermediate coat 331.Even when any one of immovable bed 121 and intermediate coat 331 comprises functional group, for example, amine, carboxyl and hydroxyl, and another is when being compound with this functional group reaction, and immovable bed 121 and intermediate coat 331 also can be coupled.
In Fig. 4 and Fig. 5 c to 5d, for example understand the method that forms immovable bed 122 and intermediate coat 331, but be not limited to this.Can form immovable bed 121 and intermediate coat 331 in advance in technology separately, they are coupled on substrate 331 then.For example, intermediate coat 331 and immovable bed 121 can be coupled in advance, and to form the compound by following structural formula 4 expressions, the compound of Xing Chenging can be coupled with substrate 331 then.
＜structural formula 4 〉
(R wherein
1Be alkyl, aryl, alkoxyl group, nitrile, ester, phenyl, hydroxyl, aliphatics lactone, cycloalkyl or thiazolinyl,
R
2Be alkyl, aryl, alkoxyl group, nitrile, ester, phenyl, hydroxyl, aliphatics lactone, cycloalkyl or thiazolinyl and
R
3Be alkyl).
For example, if substrate 331 is hydroxyls, so with intermediate coat 331 and immovable bed 121 coupled Si (OR by the compound of structural formula 4 expressions
3)
3Base can be coupled with the hydroxyl of substrate.The intermediate coat 331 that forms can provide freely interacting of low polymer probe and target sample, and hydridization for example is as junctor in the low polymer probe array or spacer.
Shown in Fig. 5 e and Fig. 5 f, can expose at least a portion of the intermediate coat 331 of formation, have the intermediate coat 331a and the intermediate coat 331b (S50) that comprises by the chemical structure of structural formula 1 expression of hydroxyl exposed region with formation.In order to make shown in Fig. 3 d, can expose the intermediate coat 331 that a part forms according to the low polymer probe array 303 of one exemplary embodiment.If expose the intermediate coat 331 that a part forms, so only the specific region of intermediate coat 331 can optionally be coupled with low polymer probe.This part area exposed can be corresponding to can with the intermediate coat 331a of low polymer probe 160 coupled region of activation A in the intermediate coat 331, and unexposed zone can be corresponding to can not with the intermediate coat 331a of low polymer probe 160 coupled region of activation B.
Can at least a portion of intermediate coat 331 be exposed by wavelength at the light of about 190nm to about 450nm scope.Be used for exposing be used to be coupled the light to the unstable protecting group of light of low polymer probe can be greater than about 340nm.In S50, except the light that when using unstable protecting group, uses, also can use the light of about 248nm to light, can increase the relative high integrated of decomposition and auxiliary low polymer probe array thus.Here, the wavelength zone of exposure intermediate coat 331 can be different from the wavelength region may of deblocking to the unstable protective material base of light, makes intermediate coat 331 can not damage in the technology of this protecting group of deblocking.Yet according to the manufacture method and the technology of low polymer probe array, the wavelength zone of exposure intermediate coat 331 can be identical with the wavelength zone that deblocks to the unstable protecting group of light.
Chemical structure by structural formula 1 expression can comprise the diazonium ketone group.If the radiation exposure of about 193nm or about 248nm is on the intermediate coat 331 that comprises the diazonium ketone group, then diazo can form carboxylic acid by the series reaction shown in following scheme 1.
＜scheme 1 〉
Expose intermediate coat 331 as fruit part, then intermediate coat 331 can separate the intermediate coat 331a and the intermediate coat 331b that comprises by the chemical structure of structural formula 1 expression of the carboxyl that comprises exposure by exposure.The intermediate coat 331a that comprises carboxyl can be corresponding to the region of activation A of substrate 311, and comprise can be corresponding to the disactivation district B of substrate 311 by the intermediate coat 331b of the chemical structure of structural formula 1 expression.
Although be not shown among the figure, the carboxyl of intermediate coat 331a can have the protecting group that is connected in this.Protecting group refers to and prevents or hinder the attachment point that participates in chemical reaction, and goes protection to refer to that protecting group is separated with attachment point so that this position participation chemical reaction.For example; the protecting group of acid instability or photo-labile can be attached to intermediate coat 331 bonded carboxyls with the defencive function base; then with junctor or be used for being removed before the original position photoetching synthetic monomer coupling of low polymer probe; or coupling synthetic low polymer probe 160, expose functional group thus.
Shown in Fig. 5 g, junctor 140 can with corresponding to the intermediate coat 331a of region of activation A coupling (S60).With the intermediate coat 331a coupled junctor 140 that comprises carboxyl, can have can with the functional group of carboxyl reaction.By making the carboxyl coupling of junctor 140 and intermediate coat 331a, can have chemical structure by following structural formula 2 expressions corresponding to the intermediate coat 331a of the region of activation of substrate 311.
＜structural formula 2 〉
(R wherein
1Be alkyl, aromatic base, alkoxyl group, nitrile, ester, phenyl, hydroxyl, aliphatics lactones, cycloalkyl or cycloalkenyl group,
R
2Be alkyl, aromatic base, alkoxyl group, nitrile, ester, phenyl, hydroxyl, aliphatics lactones, cycloalkyl or cycloalkenyl group,
Y be with junctor coupled position and
X is directly or via immovable bed and substrate coupled position).
Although be not shown among the figure, can adhere to protecting group with coupled connector 140 effectively.As previous argumentation, protecting group refers to and prevents or hinder the attachment point that participates in chemical reaction, and goes protection to refer to that protecting group is separated with attachment point so that this position participation chemical reaction.Thereafter, shown in Fig. 5 h, low polymer probe 160 can with junctor 140 coupling (S70).Low polymer probe 160 can be described as being used for low polymer probe array 100 according to one exemplary embodiment with reference to figure 2a, thus should the descriptions thereof are omitted.Low polymer probe 160 can be coupled with junctor 140, and the covalent linkage in the meeting realization chemical bond that should be coupled.Low polymer probe 160 refers to the monomer that synthesizes to come synthesis of oligonucleotides physical prospecting pin 160 by original position with junctor 140 couplings.Although be not shown among the figure, can connect protecting group and be used for the monomer of low polymer probe 160 synthetic low polymer probes to be coupled effectively.As previous argumentation, protecting group refers to and prevents or hinder the attachment point that participates in chemical reaction, and goes protection to refer to that blocking group separates with attachment point so that this position participation chemical reaction.
As the specific examples of low polymer probe 160, will describe in detail and utilize original position photoetching synthetic oligonucleotide probe.Can expose the functional group of junctor 140, then with the nucleoside phosphoramidites monomer of the protecting group bonding of photo-labile can with the functional group coupling that exposes.Can the sealing-in of nonactive ground not participate in the coupled functional group, and to carry out oxidation be the phosphoric acid salt structure with conversion phosphorous acid two ester structures, its can by phosphoramidite and 5 '-bonding between the hydroxyl forms.As mentioned above; can repeat in proper order the junctor 140 on the A of region of activation the monomeric coupling of going to protect, have desired order, do not participate in the nonactive sealing-in of coupled functional group and convert the oxidation of phosphoric acid salt structure to, with synthetic oligonucleotide probe 160 on each region of activation A with desired order.
With reference to figure 1a to 3d, the description based on according to the low polymer probe array 303 of one exemplary embodiment uses description to make method and low polymer probe array according to the substrat structure of one exemplary embodiment.Identical reference marker is represented components identical in each figure of embodiment, has omitted the detailed description of this element thus.
Be used for manufacture method and the method that is used to make according to the low polymer probe of one exemplary embodiment, can comprise at least one step of the method for omitting the low polymer probe that is used for the one exemplary embodiment shown in the shop drawings 5a-5h according to the substrat structure of one exemplary embodiment.Although described each element, will omit according to the mutual component in the description of the low polymer probe array 303 of the one exemplary embodiment shown in Fig. 3 d.
As shown in Figure 1a, according to the method for one exemplary embodiment manufacturing substrat structure 100, can comprise the intermediate coat 130 that substrate 110 (S10) is provided and on the substrate 110 that forms, comprises the chemical structure of representing by structural formula 1.Shown in Fig. 1 b, make the method for substrat structure 101 according to one exemplary embodiment, can comprise substrate 110 (S10) is provided, on the immovable bed 120 that immovable bed 120 is being provided on the substrate 110 that forms and is forming, forms the intermediate coat 130 that comprises by the chemical structure of structural formula 1 expression.
Shown in Fig. 1 c, make the method for substrat structure 102 according to one exemplary embodiment, can comprise the three-dimensional surface (S20) that substrate 110 (S10) is provided, forms substrate 110, on the three-dimensional surface of the substrate 111 that forms, form immovable bed 121 (S30) and on immovable bed 121, form the intermediate coat 131 (S40) that comprises by the chemical structure of structural formula 1 expression.
Shown in Fig. 2 a, make the method for low polymer probe array 200 according to one exemplary embodiment, can comprise and substrate 110 (S10) is provided, on substrate 110, provides to form and comprise by the chemical layer (S40) of the intermediate coat of the chemical structure of structural formula 1 expression, expose the whole surface of the chemical layer that forms intermediate coat, expose carboxyl (S50) thus, and make the carboxyl and low polymer probe 160 couplings (S70) of the exposure of intermediate coat 230.Can expose the whole surface of intermediate coat 230, and low polymer probe 160 can comprise can with the carboxyl coupled functional group of intermediate coat.As a result, the intermediate coat 230 of low polymer probe array 200 can comprise the structure by following structural formula 2 expressions.
＜structural formula 2 〉
(wherein R1 is alkyl, aromatic base, alkoxyl group, nitrile, ester, phenyl, hydroxyl, aliphatics lactones, cycloalkyl or cycloalkenyl group,
R2 is alkyl, aromatic base, alkoxyl group, nitrile, ester, phenyl, hydroxyl, aliphatics lactones, cycloalkyl or cycloalkenyl group,
Y be with low polymer probe coupled position and
X is directly or via immovable bed and substrate coupled position).
Shown in Fig. 2 c, make the method for substrat structure 202 according to one exemplary embodiment, can comprise the three-dimensional surface (S20) that substrate 110 (S10) is provided, forms substrate 110, on the substrate 111 of three-dimensional surface, form immovable bed 121 (S30), on immovable bed 121, form and comprise by the intermediate coat 231 (S40) of the chemical structure of structural formula 1 expression, expose the whole surface of intermediate coat 231, expose carboxyl (S50) thus, and make the intermediate coat 230 and low polymer probe 160 couplings (S70) of exposure.
Shown in Fig. 2 d, make the method for substrat structure 203 according to one exemplary embodiment, can comprise the three-dimensional surface (S20) that substrate 110 (S10) is provided, forms substrate 110, form immovable bed 121 (S30) on the substrate with three-dimensional surface 111, on immovable bed 121, forming and comprise by the intermediate coat 231 (S40) of the chemical structure of structural formula 1 expression, expose the whole surface of intermediate coat 231, expose carboxyl (S50) thus, make the carboxyl and junctor 140 couplings (S60) of exposure, and make junctor 140 and low polymer probe 140 couplings (S70).Junctor can have can with the functional group of carboxyl reaction on the intermediate coat 231.
Shown in Fig. 3 a, manufacture method according to the low polymer probe array 300 of one exemplary embodiment, can comprise substrate 310 (S10) is provided, form be used in comprise on the substrate 310 by the chemical layer (S40) of the intermediate coat of the chemical structure of structural formula 1 expression, the part that exposes chemical layer be used to form intermediate coat have with separation exposure carboxylic acid intermediate coat 330a and comprise intermediate coat 330b, and the intermediate coat 330 and low polymer probe 160 couplings (S70) that make carboxylic acid with exposure by the chemical structure of structural formula 1 expression.Can partly expose intermediate coat 230, and low polymer probe 160 can comprise on the intermediate coat can with carboxyl coupled functional group.Low polymer probe 160 can be not and the whole surface coupling of intermediate coat 330, but expose predetermined or given regional 330a by part, and the region of activation 330a that selects is provided thus.Thus, each low polymer probe can react more knifeedge with target sample.Intermediate coat 330 can be used as the junctor (link molecule) that connects substrate 310 and low polymer probe 160 and/or is used to provide spacer with the space allowance of target sample hydridization needs.
Shown in Fig. 3 b, manufacture method according to the low polymer probe array 301 of one exemplary embodiment, can comprise substrate 310 (S10) is provided, on the substrate 310 that forms, provide immovable bed 120 (S30), the chemical layer (S40) that forms the intermediate coat 231 that comprises the chemical structure of being represented by structural formula 1 is provided on the immovable bed 120 that forms, the part that exposure is used to form the chemical layer of intermediate coat has the intermediate coat 330a and the intermediate coat 330b (S50) that comprises by the chemical structure of structural formula 1 expression of the carboxylic acid of exposure with separation, and the intermediate coat 330a and low polymer probe 160 couplings (S70) that make the carboxylic acid with exposure.
Shown in Fig. 3 c, manufacture method according to the low polymer probe array 302 of one exemplary embodiment, can comprise substrate 310 (S10) is provided, form the three-dimensional surface (S20) of substrate 310, on substrate, form immovable bed 121 (S30) with three-dimensional surface 311, on immovable bed 121, form the chemical layer (S40) of the intermediate coat that comprises the chemical structure of representing by structural formula 1, the part of chemical layer that exposure is used to form intermediate coat is with the intermediate coat 331a that intactly separates the carboxylic acid with exposure and comprise intermediate coat 331b (S50) by the chemical structure of structural formula 1 expression, and the intermediate coat 330a that makes the carboxylic acid with exposure and low polymer probe 160 be coupled (S70).
Can obtain better understanding according to following experimental embodiment, and undocumented composition also can be by those skilled in the art will readily understand here to one exemplary embodiment.
＜experimental example 1: make substrat structure〉with three-dimensional surface
Utilize spin coating proceeding on silicon substrate, to apply XP4739 (Rohm ﹠amp as silicone resin; Haas Electronic Materials) cured firmly about 60 seconds to the thickness of about 90nm, and at about 250 ℃.On substrate with about 2000rpm with the thickness that I7010 is spin-coated to about 1.2mm, cured about 60 seconds at about 100 ℃ then.Utilization has the black tone mask of the checkerboard pattern type of about 11mm opening size, in ASML PAS5500100D equipment with the projection process product and be exposed to the light of about 365nm wavelength.With the aqueous solution development product of about 2.38%TMAH, to open length and width straight line zone intersected with each other.At CF
4Under the atmosphere surrounding substrate is carried out plasma etching, partly remove siloxanes, peel off by skiving then and remove remaining photoresist mask with development from photo-resist.With the sulphur acid-treated product activating hydroxyl, and utilize TEL Mark 8 Act trace with about 50rmp with the toluene solution spin coating of about 0.1% amino triethoxy propyl silane about 60 seconds of this substrate that is coupled, dry then about 14 minutes.
Cured product about 40 minutes at about 120 ℃, washed about 10 minutes with DI water then, utilized ultrasonoscope (sonicator) about 15 minutes, washed about 10 minutes with DI water then.At TELMark 8Act trace with acetonitrile wash product about 60 second thereafter.Be coupled about 60 seconds of the EtOH solution of N-(3-triethoxy propyl group)-4-maloyl group amine of about 0.1% of about 50rmp spin coating,, solidified about 10 minutes at about 110 ℃ then with the IPA flushing.Utilize TEL Mark 8 Act trace, with about 10ml join substrate at the dissolved nitrophenyl propoxycarbonyl TEG-cyano ethyl phosphoramidite of about 1mM and about 5mM and the acetonitrile solution of tetrazolium respectively, and remained under the normal temperature about 5 minutes.With about 1000rpm under rotation with the acetonitrile treatment product removing unreacted material, and remove remaining solvent with about 2500rpm by Rotary drying.
＜experimental example 2: make immovable bed 〉
Growth PAD oxide compound is to about 1000 on the silicone resin substrate
Thickness.On the substrate with about 2000rpm rotary coating BC70KrF Nega PR and under about 100 ℃, cured about 60 seconds.Utilization has the black tone mask of the checkerboard pattern type of about 11mm opening size, also exposes by the light of about 248nm wavelength with the projection process product in having the ASML exposure sources of KrF light source.TMAH aqueous solution development product with about 2.38% is to open length and width straight line zone intersected with each other.At CF
4Under the atmosphere surrounding substrate is carried out plasma etching to remove the photo-resist part of developing, peel off by skiving then and remove remaining photoresist mask, open the PAD oxide areas of patterning thus.About 120 ℃ with piranha (thiosulfonic acid: hydrogen peroxide=about 70: about 30) handle about 1 hour of product to activate the hydroxyl of the PAD oxide areas that will form array.Comprise the diazonium ketone group silane compound can with the hydroxyl reaction of silicone resin substrate to form single film.Silane compound is dissolved in the toluene, is immersed in then on the surface of silicone resin to react under about 100 ℃ about 24 hours to about 48 hours.
＜experimental example 3: the synthetic compound that is used to comprise the intermediate coat of diazonium ketone group 〉
(1) synthesizing methyl (5-norbornene)-3-oxo-propionic ester
With reference to following scheme 2, in ethyl ether, cyclopentadiene is added to the solution of methyl vinyl ketone, and approximately reacting about 12 hours under the room temperature.Remove solvent, and under vacuum product of distillation to obtain pure 2-ethanoyl-5-norbornylene.Methylcarbonate and sodium hydride are put into the flask that comprises the THF that has nitrogen in proper order.Under agitation slowly add 2-ethanoyl-5-norbornylene.This mixture reacted about 24 hours down at about 80 ℃, used acidifying with acetic acid then.Remove solvent, utilize water and ethyl ether to extract residue then.With the organic layer of sodium chloride solution flushing extraction, and at MgSO
4Drying is removed this solvent then.Product of distillation is to obtain pure methyl (5-norbornene)-3-oxo-propionic ester under vacuum.
＜scheme 2 〉
1HNMR
(CDCl3, ppm): 5.82-6.14 (2H, interior-the olefinic proton, outer-the olefinic proton), 3.7 (3H ,-OCH3), 3.15-3.53 (2H, α-hydrogen), 2.9-3.0 (2H), and 1.24-1.9 (5H) .13CNMR (CDCl3, ppm): 204 (C=O, ketone), 167 (COO-, esters), 131-138 (C=C), 27.62-52.27 (aliphatic carbon) .FT-IR (NaCl plate, cm-1): 1755 (C=O, ketone), 1712 (COO-, ester), 1625 (C=C, vinyl).
(2) synthesizing methyl (5-norbornene)-2-diazonium-3-oxo-propionic ester
With reference to following scheme 3, acetonitrile is poured in the flask, methyl (5-norbornene)-3-oxo-propionic ester is made an addition to this, and cool off with frozen water at about 0 ℃.Triethylamine is slowly made an addition to this, and will carboxyl benzenesulfonyl trinitride be added to this mixture as diazo transfer reagent.Kept this mixture about 15 minutes down at about 0 ℃, and approximately reacting about 2 hours under the room temperature.Remove this solvent, and utilize water and Petroleum ether extraction residue.The petroleum ether layer that filter to extract with spectral filter, and remove solvent, and under vacuum dried residue to obtain methyl (5-norbornene)-2-diazonium-3-oxo-propionic ester.
＜scheme 3 〉
1H NMR (CDCl3, ppm): 5.82-6.20 (2H, interior-the olefinic proton, outer-the olefinic proton), 3.7 (3H ,-OCH3), 2.9-3.0 (2H), 1.24-1.9 (5H) .13C NMR (CDCl3, ppm): 194 (C=O, ketone), 161 (COO-, ester), 131-138 (C=C), 27.62-52.27 (aliphatic carbon) .FT-IR (NaCl plate, cm-1): 2139 (N2, diazoes), 1722 (C=O, ketone), 1651 (COO-, esters).
＜experimental example 4: on immovable bed, form intermediate coat 〉
On substrate, form triethoxy (10-undecenyl)-silane as immovable bed.The hydroxyl of 2-(13-hydroxyl-2-oxygen tridecyl)-purine and the 2-diazonium-3-oxo-hexanolic acid ester methane reaction that comprises the diazonium ketone group are to form intermediate coat.Carry out Diels-Alder reaction as the alkene of the immovable bed of diene base with as 2-(13-hydroxyl-2-oxygen the tridecyl)-purine of dienophile, on immovable bed, to form intermediate coat, as follows.
＜experimental example 5: form spacer 〉
In experimental example 4, the intermediate coat that utilizes the exposure of ASML PAS5500 100D stepper selectivity to form forms spacer thus on the intermediate coat of the carboxyl with exposure.Utilization is used to prolong the TEL Mark 8 Act track of spacer, to wherein add substrate at the acetonitrile solution of about 10ml of about 1mM and about 5mM dissolved nitrophenyl propoxycarbonyl TEG-cyano ethyl phosphoramidite and tetrazolium respectively, and remained under the normal temperature about 5 minutes.Removing unreacted material, and remove remaining solvent by Rotary drying with about 1000rpm rotation product with about 2500rpm.The flushing residue is to have with the wetting substrate of acetonitrile.
＜experimental example 6: growth nucleic acid 〉
Utilize the ASML PAS5500 100D stepper of about 248nm or about 365nm wavelength to occur therein carrying out photoresponse on the zone of nucleic acid reaction, carry out subsequent reaction then.Utilize TEL Mark 8 Act track, will be wherein respectively at the acetonitrile solution processing substrate of about 10ml of about 1mM and about 5mM lytic gland purine/thymus pyrimidine/guanine/cytosine(Cyt) sugar-phosphoramidite and tetrazolium, and remained under the normal temperature about 5 minutes.With about 1000rpm under rotation with the acetonitrile treatment product removing unreacted material, and remove remaining solvent by Rotary drying with about 2500rpm.Utilize TEL Mark 8 Act track, the iodine solution of about 0.02M is handled substrate among the solution of usefulness Ac2O/py/ Methylimidazole (1: 1: 1) and the THF in THF, with sealing-in and the oxidation that does not connect nucleic acid.Thereafter, beginning nucleic acid by photoactivation synthesizes.On quartz mask, utilize checkerboard pattern chromium, under the ASML of about 365nm wavelength PAS5500100D stepper, expose, remove nitryl aromatic family protecting group thus with the energy of about 5000mJ with about 11 μ m opening sizes.By utilizing VITAMIN B4/thymus pyrimidine/guanine/cytosine(Cyt) sugar-phosphoramidite, repeat coupling, termination, oxidation and light and go protection, synthetic thus nucleic acid with desired order.
As mentioned above, can improve the integrated and reaction yield of low polymer probe array according to substrat structure, low polymer probe array and the manufacture method thereof of one exemplary embodiment.Intermediate coat in substrat structure and the low polymer probe array can be used as junctor or spacer, because intermediate coat can provide optionally the zone with the low polymer probe reaction.Intermediate coat can have low winding, and can make reactive group in about 248nm and carboxyl reaction, produces significantly high decomposition thus.
Although described one exemplary embodiment, it will be apparent to one skilled in the art that and to carry out various modifications and change to it, and do not break away from the scope and spirit of one exemplary embodiment together with one exemplary embodiment.Therefore, should be understood that above embodiment is not restrictive, but be illustrative in all respects.
Claims (25)
1. substrat structure comprises:
Substrate; With
On described substrate, comprise intermediate coat by the chemical structure of following structural formula 1 expression.
＜structural formula 1 〉
(R wherein
1Be alkyl, aromatic base, alkoxyl group, nitrile, ester, phenyl, hydroxyl, aliphatics lactones, cycloalkyl or cycloalkenyl group,
R
2Be alkyl, aromatic base, alkoxyl group, nitrile, ester, phenyl, hydroxyl, aliphatics lactones, cycloalkyl or cycloalkenyl group and
X directly or via immovable bed is coupled with described substrate).
2. according to the substrat structure of claim 1, wherein, described immovable bed comprises-Si (OR)
3(wherein R is an alkyl).
3. according to the substrat structure of claim 1, wherein, R
1Or R
2Be by to be selected from by
The expression compound dialkylene and be selected from by
The dienophile of the compound of expression carries out Diels-Alder reaction and forms.
4. according to the substrat structure of claim 1, wherein, described substrate is included on the described substrate or the three-dimensional surface in the described substrate, and described intermediate coat is on described three-dimensional surface.
5. low polymer probe array comprises:
Substrate; With
Be formed on the low polymer probe on the described substrate, the centre of wherein said low polymer probe and described substrate has the chemical structure by 2 expressions of following structural formula.
＜structural formula 2 〉
(R wherein
1Be alkyl, aromatic base, alkoxyl group, nitrile, ester, phenyl, hydroxyl, aliphatics lactones, cycloalkyl or cycloalkenyl group,
R
2Be alkyl, aromatic base, alkoxyl group, nitrile, ester, phenyl, hydroxyl, aliphatics lactones, cycloalkyl or cycloalkenyl group,
Y and junctor, spacer or low polymer probe coupling and
X directly or via immovable bed is coupled with described substrate).
6. according to the low polymer probe array of claim 5, wherein, described immovable bed comprises-Si (OR)
3(wherein R is an alkyl).
7. according to the low polymer probe array of claim 5, wherein, R
1Or R
2Be by to be selected from by
The compound of the group that the compound of expression is formed be selected from by
The compound of the group that the compound of expression is formed carries out Diels-Alder reaction and forms.
8. according to the low polymer probe array of claim 5, wherein, described substrate is included on the above-mentioned substrate or the three-dimensional surface in the described substrate, and intermediate coat is on described three-dimensional surface.
9. according to the low polymer probe array of claim 5, wherein, junctor or spacer further are inserted between described intermediate coat and the low polymer probe.
10. according to the low polymer probe array of claim 5, wherein, described substrate comprises with low polymer probe coupled region of activation and does not have and low polymer probe coupled disactivation district, have chemical structure between low polymer probe on the described region of activation and the described substrate, and have chemical structure between low polymer probe in the described disactivation district and the described substrate by 1 expression of following structural formula by structural formula 2 expressions.
＜structural formula 1 〉
＜structural formula 2 〉
(R wherein
1Be alkyl, aromatic base, alkoxyl group, nitrile, ester, phenyl, hydroxyl, aliphatics lactones, cycloalkyl or cycloalkenyl group,
R
2Be alkyl, aromatic base, alkoxyl group, nitrile, ester, phenyl, hydroxyl, aliphatics lactones, cycloalkyl or cycloalkenyl group,
Y and junctor, spacer or low polymer probe coupling and
X directly or via immovable bed is coupled with described substrate).
11. the low polymer probe array according to claim 10 further comprises:
At the low polymer probe on the described region of activation and junctor between the intermediate coat and spacer.
12. a method of making substrat structure comprises:
Substrate is provided; With
On described substrate, form the intermediate coat that comprises by the chemical structure of following structural formula 1 expression.
＜structural formula 1 〉
(R wherein
1Be alkyl, aromatic base, alkoxyl group, nitrile, ester, phenyl, hydroxyl, aliphatics lactones, cycloalkyl or cycloalkenyl group,
R
2Be alkyl, aromatic base, alkoxyl group, nitrile, ester, phenyl, hydroxyl, aliphatics lactones, cycloalkyl or cycloalkenyl group and
X directly or via immovable bed is coupled with described substrate).
13. according to the method for the manufacturing substrat structure of claim 12, wherein, described immovable bed comprises-Si (OR)
3(wherein R is an alkyl).
14. according to the method for the manufacturing substrat structure of claim 12, wherein, R
1Or R
2Be by to be selected from by
The compound of the group that the compound of expression is formed and be selected from by
The compound of the group that the compound of expression is formed carries out Diels-Alder reaction and forms.
15. according to the method for the manufacturing substrat structure of claim 12, wherein, described substrate is included on the described substrate or the three-dimensional surface in the described substrate, and described intermediate coat is formed on the described three-dimensional surface.
16. according to the method for the manufacturing substrat structure of claim 12, wherein by the chemical structure of structural formula 1 expression by by being prepared as follows:
Be selected from by
In the group that the compound of expression is formed one and be selected from by
One in the group that the compound of expression is formed is carried out Diels-Alder reaction and is used for cyclisation, with the synthetic diketone that comprises the diketo structure; With
By making the diketone and the reaction of diazonium transfering reagent that comprise the diketo structure form the diazonium ketone group.
17. according to the method for the manufacturing substrat structure of claim 16, wherein, described diazonium transfering reagent is to carboxyl benzenesulfonyl trinitride, p-toluenesulfonyl trinitride or to the dodecylbenzene sulfuryl azide.
18. a method of making low polymer probe array comprises:
Make substrat structure as claimed in claim 12;
Expose at least a portion of described intermediate coat; With
Make at least a portion and the low polymer probe coupling of the described intermediate coat of exposure.
19., wherein, at least a portion of described intermediate coat is exposed to wavelength at the light of about 190nm to about 450nm scope according to the method for the manufacturing low polymer probe array of claim 18.
20. according to the method for the manufacturing low polymer probe array of claim 18, wherein, described immovable bed comprises-Si (OR)
3(wherein R is an alkyl).
21. according to the method for the manufacturing low polymer probe array of claim 18, wherein, R
1Or R
2Be by to be selected from by
The compound of the group that the compound of expression is formed and be selected from by
The compound of the group that the compound of expression is formed carries out Diels-Alder reaction and forms.
22. according to the method for the manufacturing low polymer probe array of claim 18, wherein, described substrate is included on the described substrate or the three-dimensional surface in the described substrate, and described intermediate coat is formed on the described three-dimensional surface.
23. according to the method for the manufacturing low polymer probe array of claim 18, wherein by the chemical structure of structural formula 1 expression by by being prepared as follows:
Be selected from by
One of them of the group that the compound of expression is formed and be selected from by
One of them of the group that the compound of expression is formed carried out Diels-Alder reaction and is used for cyclisation, with the synthetic diketone that comprises the diketo structure; With
Form the diazonium ketone group by diketone and the reaction of diazonium transfering reagent that comprises the diketo structure.
24. according to the method for the manufacturing low polymer probe array of claim 23, wherein, described diazonium transfering reagent is to carboxyl benzenesulfonyl trinitride, p-toluenesulfonyl trinitride or to the dodecylbenzene sulfuryl azide.
25., wherein, at least a portion and the low polymer probe coupled step of the described intermediate coat of exposure are comprised via junctor or spacer coupling according to the method for the manufacturing low polymer probe array of claim 18.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020070014534A KR100843147B1 (en) | 2007-02-12 | 2007-02-12 | Substrate for oligomer probe array, oligomer probe array and the method of fabricating the same |
| KR10-2007-0014534 | 2007-02-12 |
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| CN101294216A true CN101294216A (en) | 2008-10-29 |
| CN101294216B CN101294216B (en) | 2013-03-20 |
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| Country | Link |
|---|---|
| US (1) | US20080214409A1 (en) |
| EP (1) | EP1958690A1 (en) |
| JP (1) | JP4837689B2 (en) |
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| CN103681236A (en) * | 2012-08-31 | 2014-03-26 | 细美事有限公司 | Substrate treating method |
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| KR101478540B1 (en) * | 2007-09-17 | 2015-01-02 | 삼성전자 주식회사 | Biosensor using nanoscale material as a channel of transistor and method of fabricating the same |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| DE3900736A1 (en) * | 1989-01-12 | 1990-07-26 | Hoechst Ag | POSITIVELY WORKING RADIATION-SENSITIVE MIXTURE CONTAINING A MULTI-FUNCTIONAL (ALPHA) -DIAZO- (BETA) -KETOESTER, METHOD FOR THE PRODUCTION THEREOF AND RADIATION-SENSITIVE RECORDING MATERIAL COMPRISING THIS MIXTURE |
| WO1998030575A1 (en) * | 1997-01-08 | 1998-07-16 | Proligo Llc | Bioconjugation of macromolecules |
| AT406667B (en) * | 1997-05-14 | 2000-07-25 | Oswald Wolfgang Ing | PACKAGING AND METHOD FOR PRODUCING THE SAME |
| US7427678B2 (en) * | 1998-01-08 | 2008-09-23 | Sigma-Aldrich Co. | Method for immobilizing oligonucleotides employing the cycloaddition bioconjugation method |
| US6258454B1 (en) * | 1998-09-01 | 2001-07-10 | Agilent Technologies Inc. | Functionalization of substrate surfaces with silane mixtures |
| US20030148360A1 (en) * | 1999-01-29 | 2003-08-07 | Surmodics, Inc. | Replicable probe array |
| JP2001178472A (en) * | 1999-12-27 | 2001-07-03 | Fuji Photo Film Co Ltd | Method for immobilizing dna fragment to surface of solid- phase carrier and dna chip |
| WO2001094032A1 (en) * | 2000-06-02 | 2001-12-13 | Eppendorf Ag | Method for producing surface-functionalized supports used as starting products for microarrays, for immobilizing biomolecules |
| WO2001098458A2 (en) * | 2000-06-19 | 2001-12-27 | Zyomyx, Inc. | Methods for immobilizing polypeptides |
| JP2003130879A (en) * | 2001-10-26 | 2003-05-08 | Fuji Photo Film Co Ltd | Dna chip |
| KR100450191B1 (en) * | 2001-12-28 | 2004-10-02 | 삼성에스디아이 주식회사 | Substrate for immobilizing physiological material, and a method of preparing the same |
| JP2004144630A (en) * | 2002-10-25 | 2004-05-20 | Nikon Corp | Organic molecule detection element and organic molecule detection apparatus |
| KR100580642B1 (en) * | 2004-01-12 | 2006-05-16 | 삼성전자주식회사 | A method for immobilizing a biomolecule to a solid substrate at a high density by using a substrate having an activated carboxyl group at the surface thereof and microarray produced using the same |
| KR100657907B1 (en) * | 2004-11-03 | 2006-12-14 | 삼성전자주식회사 | Novel linker compound, a substrate coated with the compound, method for producing a microarray using the compound and a microarray produced by the mehtod |
-
2007
- 2007-02-12 KR KR1020070014534A patent/KR100843147B1/en not_active IP Right Cessation
-
2008
- 2008-02-11 US US12/068,715 patent/US20080214409A1/en not_active Abandoned
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| CN103681236A (en) * | 2012-08-31 | 2014-03-26 | 细美事有限公司 | Substrate treating method |
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| US20080214409A1 (en) | 2008-09-04 |
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| JP4837689B2 (en) | 2011-12-14 |
| CN101294216B (en) | 2013-03-20 |
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